Interleukin (IL) 12, formerly termed natural killer cell-stimulatory factor or cytotoxic lymphocyte maturation factor, is a disulfide-linked heterodimeric cytokine composed of 35-and 40-kDa subunits; the subunits are commonly designated "p35" and "p40". The complimentary DNAs encoding the p35 and p40 subunits from both the mouse and humans have been sequenced and cloned, and both human and mouse IL-12 have been shown to act as growth factors for natural killer ("NK") cell and T-cell, in vitro and in vivo. Furthermore, IL-12 has also proven to be effective in regression and complete disappearance of murine tumors. Tahara et al., Cancer Research 54 (1): 182-9, 1994; Brunda et al., J. EXP. MED. 178 (4): 123-30, 1993.
However, because IL-12 has a short half life in vivo, frequent injections of the cytokine are needed to achieve therapeutic effects. Moreover, relatively large quantities of IL-12 (in the range of 1-10 .mu.g/day) are typically required. Therefore, administration of recombinant IL-12 often resulted in toxicity.
IL-12 gene therapy using retroviral vectors is underway in several laboratories, and its anti-tumor effect has been demonstrated. Lotze, M. T., et al., J. Cell. Biochem., p.184, 1993.; Robbins, et al., Cancer Gene Therapy 1(2):147, 1994. In the Lotze, et al. study, the genes for IL-12 p35 and p40 subunits were inserted into NIH 3T3 fibroblasts. The fibroblasts were used to deliver IL-12 at the site of tumors, delaying growth of a variety of murine tumors. In the Robbins, et al. study, the direct delivery of IL-12 to several different mouse tumor lines by retroviral-mediated transduction prior to inoculation or to fibroblasts that were then coadministered with tumor cells resulted in inhibition of tumor growth as well as in the induction of antitumor immunity.
However, to date, it was not possible to cause reliable regression of established tumors and their spontaneous metastases using direct IL-12 gene therapy.